Diabetic patients develop podocytopathy due to the loss of podocyte function caused by dedifferentiation and cell death (apoptosis), or both. In injury mode, podocytes dedifferentiate- loss of their molecular markers (WT1 and nephrin) and gain of parietal epithelial cell markers such as PAX2 and claudin 1. High glucose milieu is known to enhance dedifferentiation and apoptosis of podocytes both in vitro and in vivo studies. Kidney cells including podocytes and tubular cells express apolipoprotein (APO) L1, however, the role of APOL1 expression in kidney cell function is not clear. The objective of the current proposal is to determine the role of APOL1 in the maintenance of podocyte integrity in high glucose milieu. The long-term goal is to utilize the optimized expression of APOL1 by podocytes as a therapeutic strategy to prevent and/or slow down the progression of diabetic podocytopathy. In preliminary studies, high glucose enhanced microRNA (miR)193a but down regulated APOL1 expression in podocytes; interestingly, miR193a and APOL1 displayed inverse feedback relationship. Since miR193a negatively regulates WT1, a transcription factor for podocyte differentiating markers, miR193a-APOL1 axis would also participate in the regulation of differentiation status in podocytes. In preliminary studies, both down regulation of miR193a and upregulation of APOL1 provided protection against high glucose mediated dedifferentiation/apoptosis in podocytes; furthermore, vitamin D receptor agonist (VDA), which down regulated miR193a and upregulated APOL1 expression, preserved podocytes integrity in high glucose milieu. Based on these findings, we hypothesize that APOL1 acts as an important component of miR193a-APOL1 axis to preserve podocyte integrity. High glucose compromises podocyte integrity through upregulation of miR193a and down regulation of APOL1, whereas, optimization of APOL1 expression would prevent and/or slow down the progression of diabetic podocytopathy. To validate our hypotheses, we will carry out the following specific aims: ? Evaluation of the role of the miR193a-APOL1 axis on PDs molecular phenotype and structural integrity ? Determination whether miR193a expression would accelerate but APOL1 expression would inhibit high glucose-induced PD injury both in vitro and in vivo ? Examination of the role of VDA in prevention and/or slow down the progression of diabetic podocytopathy with or without APOL1 expression This proposal provides mechanistic insight into the development of diabetic podocytopathy. We feel strongly that optimization of APOL1 expression in PDs could be used as a therapeutic strategy to preserve PDs molecular phenotype and structural integrity in the diabetic milieu.